The processes of protein folding, protein-protein interaction, and protein- peptide binding are fundamental to many phenomena in biological systems. The development of an understanding of these processes at a level that is useful in terms of generating accurate predictions about the free energies associated with such processes would be profound importance. The generation of this knowledge requires parallel high resolution structural studies and highly resolved thermodynamic studies. The structural studies reveal in detail the surfaces and groups that interact in the course of these processes whereas the thermodynamic studies reveal the enthalpic and entropic contributions to the free energy as a function of temperature. The comparison and correlation of these two types of data is necessary to yield the desired information that form the basis of structure based thermodynamic analysis. Models have been and are being developed that can be applied to appropriate systems. These models include some terms that are closely linked to fundamental principles and other that are parameterized based on empirical experimental data. Such models will be tested, refined, and extended through studies of a set of important systems that include metal-binding proteins, peptide-binding antibodies, actin- binding proteins and their complexes, peptide-peptide interactions, protease-inhibitor interactions, and models for the unfolded states of peptides and proteins. The techniques to be utilized include X-ray crystallography, nuclear magnetic resonance spectroscopy, titration and differential scanning calorimetry, and computational methods.